The production of maximally concentrated urine is made possible by the renal countercurrent multiplication system, which generates and maintains a hypertonic inner medulla, comprised of cortico- medullary gradients of NaCl and urea. Many features of the multiplication system remain to be elucidated, in particular the role of the medullary microcirculation. By modulating blood flow, vasa recta (i.e., the blood vessels in the renal medulla) can have a major effect on sodium and water homeostasis as well as on the long-term control of arterial blood pressure; their role in hypertension and congestive heart failure is thus highly relevant. Changes in renal medullary hemodynamics are also directly involved in pressure natriuresis. The overall goal of this research is to develop a comprehensive mathematical model of the renal medullary microcirculatory function in order to predict the efficiency of countercurrent exchange of water, small solutes, and macromolecules by the vasa recta. The specific aims of this project are the following. 1. To investigate the specific role of water channels (AQP-1) and urea transporters in descending vasa recta, incorporating data obtained on wildtype mice, AQP-1 deficient mice and AQP-1 deficient mice in which the AQP-1 gene has been replaced by means of an adenovirus. 2. To determine the mechanisms that control interstitial albumin concentration. The effects of albumin concentration polarization at the vessel walls will be determined as a first step. 3. To model the transport of oxygen in the renal medulla and to examine the effects of changes in blood flow rate and tubular consumption on oxygen tension. Medullary hypoxia is a consequence of the need for countercurrent exchange; however, too little oxygen can cause medullary hypoxic injury. 4. To examine how secretion of the vasoactive hormone nitric oxide into the vascular exchanger affects medullary blood flow and interstitial osmolality, and to investigate the relationship between the reduced medullary hematocrit, medullary hypoxia and the effectiveness of NO in the medulla.